Haemostatic Kit, A Method of Preparing A Haemostatic Agent and a Method of Promoting Haemostatis

ABSTRACT

A haemostatic kit to be used as a medical device provides for a containment unit and a haemostatic agent in said containment unit, said haemostatic agent occupying less than 90% of the volume of the containment unit. This allows for facile and consequently sterile preparation of, for instance, a gelatin paste for use in haemostatis when combined with saline, thrombin or another agent to assist in haemostatis.

This application is a continuation under 35 U.S.0 §120 of U.S. patentapplication Ser. No. 10/326,080, filed Dec. 23, 2002, which claimsbenefit of priority to U.S. Provisional Application Ser. No. 60/367,515,filed Mar. 27, 2002 and U.S. Provisional Application Ser. No.60/341,812, filed Dec. 21, 2001, the contents of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

A medical device comprising a powdered haemostatic agent in acontainment unit suitable for adding a liquid to the agent and mixingthe contents whilst still in the container allows for the sterile use ofthe haemostatic agent and greater ease of preparation. The haemostaticagent, such as collagen or a collagen-derived product such as gelatin,is present in a 1-volume in the containment unit to allow for suitablemixing of any further agents, such as water, saline, or thrombin.

BACKGROUND OF THE INVENTION

The use of haemostatic agents provides for control of bleeding insurgical procedures. Haemostatic agents supplement pressure, ligatureand other conventional methods of controlling capillary, venous, andarterial bleeding.

The present investigators have commercialised a gelatin sponge as ahaemostatic agent. A powdered agent some practical advantages in termsof surface area coverage and can be removed by irrigation and suction.Conventional powdered haemostatic agents are unpractical and risk eithercontamination of the sterile surgical field. The present inventionaddresses the risk of compromised sterility and contamination of thehaemostatic agent by providing a kit which allows for the sterile andfacile preparation of the powdered haemostatic agent.

WO 01/28603 relates to an injectable formulation for delivery of acomposition comprising an osteogenic protein and a haemostatic gelatinfoam paste as well as to a method of making a haemostatic gelatin foampaste suitable for injecting osteogenic protein, the method comprisinghydration of Gelfoam® powder with glutamic acid buffer.

U.S. Pat. No. 5,394,886 relates to a skin biopsy plug wherein the plugis a porous sponge made from gelatin material, which is implanted into awound, swells, absorbs blood, and is completely absorbed in the patient.It relates to a combination of the punch (the blade for excising skin)and the plug. The plug used is the commercially available Gelfoam®.

U.S. Pat. No. 5,645,849 claims a haemostatic patch comprising abiodegradable gelatin matrix, a haemostatic-promoting amount of thrombinand epsilon aminocaproic acid.

JP 62221357 discloses a skin ointment for promoting haemostatic effectcomprising thermoplastic resin or rubber dissolved in solvent andcontains dispersed gelatin powder. The product is an ointment comprisingthermoplastic resin or rubber and a fine powder of collagen, gelatin orchitosan.

FR 2679772 relates to particulate material to create an embolismcomprising a polymer coated with a haemostatic or thrombonic agent. Thehaemostatic agent may be a finely divided gelatin powder.

U.S. Pat. No. 6,096,309 relates to a haemostatic composition comprisingthrombin and a mixture of non-microfibrillar collagen and microfibrillarcollagen in an aqueous medium wherein the microfibrillar collagen has anaverage fibril diameter of about 3-30 nm.

U.S. Pat. No. 4,515,637 relates to both a method of forming acollagen-thrombin haemostatic composition and to a lysophilized collagenproduct, comprising collagen and thrombin.

U.S. Pat. No. 6,045,570 relates to a gelatin powder for use as ahaemostatic agent and to a biological sealant comprising a gelatinslurry which includes milled gelatin powder. The slurry preferablycomprises Gelfoam® powder mixed with a diluent selected from saline andwater. The slurry demonstrates superior flow characteristics in that itexhibits minimal dilatency and can be easily injected or introducedthrough catheter lumens, especially small lumens. The product thereforehas very fluid characteristics.

Gelfoam® is a commercially available product providing powdered gelatinfor application to bleeding surfaces as a haemostatic agent. Thepowdered gelatin is provided in a full glass jar with a metal lid or ina sachet, each of which are to be opened and the contents of which, i.e.the gelatin, are to be poured into a sterile beaker or bowl.Contamination must be avoided during this process and a steriletechnique must be employed when adding a sterile saline solution. Theproblem of dispersion is avoided by initially compressing the powderwith gloved fingers into the bottom of the beaker and then kneading itinto the desired consistency. The powder is to be used as soon as thejar or sachet is opened and unused portions are discarded. This requirespreparation of the haemostatic agent immediately prior to use.Contamination and sterility is not controlled by the product but ratherby the user and by the co-ordination of events following preparation ofthe agent.

Curacell® is a powdered haemostatic agent comprising oxidised cellulose,caboxycellulosum calcium which is applied as dry powder onto a bleedingarea.

Avitene® is a microfibullar collagen haemostat “flour” typically applieddry.

SUMMARY OF THE INVENTION

A first object of the invention relates to a medical device comprising:

i) a containment unit defining a first internal volume; said containmentunit being comprised of a material substantially impermeable to fluid;

ii) a haemostatic agent of a second volume contained in said containmentunit, said second volume being less than 90% of the first volume.

A further object of the invention relates to a haemostatic kitcomprising

i) a containment unit said containment unit defining a first internalvolume and

ii) a second volume of haemostatic agent

wherein the second volume relative to the first internal volume is suchthat the kit is suitable adding a third volume of liquid to said secondvolume and suitable for mixing said haemostatic agent within saidcontainment unit.

Moreover, the invention relates to a process for preparing a haemostaticproduct comprising the steps of:

i) providing a sterile containment unit having a first internal volumeand at least one aperture for opening and comprising a second volume ofhaemostatic agent, said second volume being no more than 90% of thefirst volume;

ii) adding a third volume of liquid to said containment unit; and

iii) mixing the haemostatic agent and the liquid by shaking thecontainment unit.

A corresponding aspect of the invention relates to a method of promotinghaemostatis comprising administering an effective amount of a putty-likepaste comprising 20 to 33% w/w of collagen to a patient in need ofhaemostatis, wherein the putty-like paste is prepared according processdefined supra.

An important object of the invention relates to the use of a containmentunit defining a first internal volume and second volume of collagen orcollagen-derived powder for the preparation of a haemostatic kit whereinthe second volume is less than 90% of the first volume.

DESCRIPTION OF THE INVENTION

The risk of compromised sterility and contamination of the haemostaticagent is addressed by the present investigators by providing a kit andmedical device which allows for the sterile and facile preparation ofthe powdered haemostatic agent. The present invention also allows forgreater flexibility and ease of preparation of the agent. Surgeons statethat the size of the bleeding area and the rate of the bleedinggenerally determine the consistency and amount of haemostatic agent.During a surgical procedure, these factors can suddenly and dramaticallychange. The present invention allows for a rapid, sterile and facilepreparation of the haemostatic agent. As stated, conventional productstypically require the surgical staff to prepare the agent in advanceusing an additional mixing container.

A first aspect of the invention relates to a medical device comprising:

i) a containment unit defining a first internal volume; said containmentunit being comprised of a material substantially impermeable to fluid;and

ii) a haemostatic agent of a second volume contained in said containmentunit, said second volume being less than 90% of the first volume.

The term “second volume” is intended to mean a volume which is a subsetwithin the first internal volume. That is to say that the second volumeof the haemostatic agent is contained within the first internal volume;that the agent is contained within the containment unit.

The medical device is preferably such that the second volume is lessthan 85%, of the first volume, preferably less than 80%, even morepreferably less than 75% of the first volume, such as less than 70%,65%, 60%, 55%, or 50% of the first volume, such as 70%, 65%, 60%, 55%,50%, 40%, 30%, 20% and 10%.

In a typical embodiment, the haemostatic agent is in powder form. In amore typical embodiment, the haemostatic agent is collagen orcollagen-derived powder. Preferably, said collagen or collagen-derivedpowder is gelatin. The gelatin may be derived from an animal or aresynthetically made (recombinant). Suitably, the gelatin originates fromporcine but may originate from other mammals. The powder is typicallysterile.

The powder is typically such that 95% of the powder is less than 1000microns in size, preferably such that 90% of the second volume is lessthan approximately 700 μm. In a further preferred embodiment, 50% volumeis less than approximately 350 μm.

The powder may be prepared from a gelatin sponge cut into pieces thatfit into a mill and that will be bulk packaged into sterilization bagsand placed in an oven (dry heat), for hardening for three hours. Thegelatin plates raw material are typically manually fed into a rotorknife mill with a sieve for final grinding. The particle size ispreferably such that not more than 5% (w/w) is retained on a 1 mm mesh.

The containment unit typically comprises at least one opening and atleast one closure-unit for closing the at least one opening. In aninteresting embodiment, the closure-unit defines a second internalvolume suitable for containing a liquid. The liquid may be present inthe closure-unit and this liquid can be released into the gelatin by amechanical or physical action.

The closure-unit may itself comprise a rupturable membrane or thecontainment unit may comprise a rupturable membrane. This membrane maydefine a physical separation between the second internal volume and theinternal volume defined by the first internal volume and may allow forthe combining of the liquid with the haemostatic agent by means ofrupturing the membrane by any physical act such as by pressure orcontact. The membrane may be ruptured (broken) by means of shaking thedevice. The rupturing of the membrane is preferably performed in such amanner so as to maintain the sterility of the liquid and of thehaemostatic agent.

Alternatively, the closure unit or containment unit may comprise arupturable membrane which is perforated in order to inject the liquid,such as to maintain sterility of the agent. In this embodiment, therupturable membrane divides the external environment from the firstand/or second internal volume. The rupturable membrane may be made ofrubber or other suitable material and be perforated by injection of theliquid through a syringe or catheter.

The containment unit may comprise of grooves, protrusions or otherphysical distortions to the otherwise parallel surfaces of thejuxtaposed walls of the containment unit so as to ameliorate orfacilitate the mixing of a liquid and the haemostatic agent.

In the embodiment wherein the haemostatic agent is collagen orcollagen-derived powder, such as gelatin, it is suitably present in anamount from about 0.1 to 50 g, preferably from about 0.2 to 20 g, evenmore preferably from about 0.4 to 10 g, most preferably from about 0.5to 5 g, such as 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 g.

The containment unit is typically substantially rigid with at least oneopening which may be closed with an appropriate closure-unit. Thecontainment unit and closure unit are typically comprised of a materialindependently selected from the group consisting of plastic, glass,metal or rigid or semi-rigid material. In a preferred embodiment, thematerial is selected from the group consisting of polypropylene,polyethylene, PVC and PET, more preferably polypropylene andpolyethylene, most preferably polyethylene. Polyethylene is mostsuitable for beta irradiation. The substantially rigid polyethylene orpolypropylene container having a single opening may be sealed with athreaded, polyethylene or polypropylene closure. The closure-unitsuitably comprises a dust-seal closure.

As stated, the containment unit defines a first internal volume;internal volume comprising a haemostatic agent of a second volume, saidsecond volume being less than 90% of the first volume. The volumedifference is, at least in part, to allow for adequate addition of athird volume and mixing of the volumes. The dimension of the containmentunit is suitably to facilitate the mixing. Typically, the dimension ofthe containment unit is also selected so as to allow for facile removalof the volumes onto the patient or other desired location. Thus, themouth of the containment unit must be suitably broad. Thus, commerciallyavailable wide-mouth or large-mouth containers are preferred.

In a particularly suitable embodiment, the haemostatic agent is presentin a volume occupied by about one gram of powder, said second volume ofhaemostatic agent is contained within a containment unit of about 50 to100 cubic centimetres, such as about 60 to 90 cubic centimetres, such asabout 70 to 80 cubic centimetres, typically about 75 cubic centimetres.

In the suitable embodiment wherein the haemostatic agent is present in avolume occupied by about two grams of powder, said second volume ofhaemostatic agent is contained within a containment unit of about 75 to200 cubic centimetres, such as about 80 to 180 cubic centimetres, suchas about 90 to 170 cubic centimetres, such as about 100 to 160 cubiccentimetres. Typically a second volume occupied by 2 g of powder iscontained within a first internal volume of 100 to 200 cubiccentimetres.

The medical device suitably further comprises iii) a third volume of aliquid. The liquid may blended with the haemostatic agent.

In a suitable embodiment, the liquid is in a unit physically separatedfrom the haemostatic agent. This physical separation may be in the formof a rigid internalised container in the containment unit or merely bymeans of a physical barrier which creates a non-porous divide betweenthe agent and the liquid.

In an alternative embodiment, the liquid is in a second containment unitwhose internal volume is physically separated from the first containmentunit, such as to form a kit.

In a suitable embodiment, the liquid is thrombin. Thus, the medical mayfurther comprise thrombin. The thrombin may be present in the firstcontainment unit or may be in a unit physically separated from thehaemostatic agent or in a second containment unit containing saidthrombin.

Thrombin, in a particularly suitable embodiment, may be added in anamount of 1-20 ml per gram of powder, such as 5-15 ml, such as 7-12 ml.

The liquid may alternatively be selected from the group consisting ofwater and an aqueous solution such as saline. Suitably, the aqueoussolution comprises an isotonicity-adjusting agent. The isotonicityadjusting agent may be sodium chloride, or known equivalents to sodiumchloride such as dextrose, various organic acids and their salts,inorganic salts such as boric acid, citric acid, tartaric acid andphosphoric acids.

The liquid may comprise thrombin and/or a bacteriostatic agent.Typically, the liquid is sterile.

In a typical embodiment, the third volume of liquid is less than 35% ofthe second volume. The volume of liquid is preferably such that, whencombined and mixed with the haemostatic agent, a doughy paste is formed.More suitably, the third volume is less than 33% of the second volume,such as less than 30%, less than 29%, less than 28%, less than 27%, lessthan 26%, less than 25%, less than 24%, less than 23%, less than 22%,less than 21%, or less than 20%.

The mixing of the liquid and the haemostatic agent is preferablyperformed by shaking the containment unit, most preferably the mixing isperformed when the at least one opening is separated from the externalenvironment by the closure-unit. Shaking may involve swirling oragitation of any kind.

In a particularly interesting embodiment, the containment unit issurrounded with on outer wrap so that the containment unit is sterile.This will allow the user to remove the outer packaging and transfer thecontainment unit into the sterile field. The user, in the sterile field,can then add the third volume of liquid, optionally by opening thecontainment unit to the external environment, adding by means ofperforating the rupturable membrane of the closure-unit or containmentunit, rupturing a seal which divides the closure unit from thecontainment unit, as discussed supra, or pouring the liquid through theat least one opening of the containment unit.

The medical device preferably further comprises an outer packagingdefining a sterile barrier seal for enclosing said containment unit andmaintaining sterility of the containment unit and its contents. Theouter packaging may be peelable or removed from the outer surface of thecontainment unit. This containment unit is preferably enclosed in anouter packaging of a flexible, semi-rigid, or rigid plastic and/ormetallic film providing a sterile barrier. The outer packaging typicallyconsists of materials selected from the group consisting ofPlastic/Aluminium foil/Plastic laminate where the plastic is selectedfrom the group consisting of PET, PE, LLDPE, CPP, PA, PETP, METPET,Tyvek and optionally bonded with an adhesive (Polyurethane or other) orco-extruded. The outer packaging preferably forms a complete barrier tomoisture.

The outer packaging may, in a particularly interesting embodiment, beable to endure radiation sterilisation at 3.5 Mrad (Beta) with abioburden of less than 100 CFU/unit. A particularly interestingembodiment of the outer packaging included a pouch of laminated foil.The laminate may be PET, such as of approximately 12 microns inthickness.

The containment unit is preferably sterile. The containment-unit-facingside of the outer packaging and the containment unit are preferablysterile.

The liquid is typically added so as to obtain a paste-like agentcomprising 20-35% wt/wt of w/w collagen powder, such as 25-33%, such as25%, 26%, 27%, 28%, 29%, 30%, 31%, 32% and 33%.

A further object of the invention relates to a haemostatic kitcomprising

i) a containment unit said containment unit defining a first internalvolume; and

ii) a second volume of haemostatic agent

wherein the second volume relative to the first internal volume is suchthat the kit is suitable to adding a third volume of liquid to saidsecond volume and suitable for mixing said haemostatic agent said mixingproceeding within the containment unit.

Preferably, the mixing occurs without present exposure to an environmentexternal to that of the containment unit, typically without exposure toa non-sterile field.

The relative volume of the second volume of haemostatic agent relativeto the first internal volume is less than in conventional products so asto be suitable for adding a third volume of liquid and for said liquidto be evenly and easily physically dispersed throughout the secondvolume of haemostatic agent. Moreover, the mixing process, whichaccelerates the dispersion of the liquid evenly throughout the secondvolume of haemostatic agent, is facilitated and ameliorated by a lowsecond volume-to-first volume ratio. Thus, in a particularly preferredembodiment, the second volume of haemostatic agent is less than 85% ofthe first internal volume, such as less than 80% of the first volume,preferably less than 75%, even more preferably less than 70% of thefirst volume 65%, 60%, 55%, or 50% of the first volume.

The mixing process occurs within the containment unit and typicallywithout present exposure to an environment external to that of thecontainment unit. That is to say that a physical barrier, such as aclosure-unit, typically separates the first internal volume, secondvolume of haemostatic agent and third volume of liquid from the externalenvironment during the mixing process.

The third volume is an amount so as to obtain a putty-like paste fromthe haemostatic agent, preferably wherein the putty-like paste of thehaemostatic agent comprises 20-35% wt/wt of w/w collagen powder, such as25-33%, such as 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32% and 33%.

The containment unit is typically rigid, comprising at least one openingand one closure-unit and such that the mixing proceeds without loss ofliquid and as described supra. The containment unit may be surrounded bya outer wrap/outer packaging se described supra.

A further aspect of the invention relates to a process for preparing ahaemostatic product comprising the steps of:

-   -   i) providing a sterile containment unit having a first internal        volume and at least one aperture for opening and comprising a        second volume of haemostatic agent, said second volume being no        more than 90% of the first volume; ii) adding a third volume of        liquid to said containment unit; and    -   iii) mixing the haemostatic agent and the liquid by shaking the        containment unit.    -   Typically, the mixing proceeds without present substantial        exposure of said haemostatic agent and said liquid to an        environment external to that the containment unit and without        exposure to a non-sterile field. Preferably, the haemostatic        agent is collagen or collagen-derived powder, typically said        collagen or collagen-derived powder comprises essentially of        gelatin.

Preferably, in the process of the invention for preparing a haemostaticproduct, said haemostatic product is in the form of a putty-like pastecomprising 20 to 99% w/w of collagen, preferably 20-80% collagen, suchas 20-75% collagen, typically 20-70% collagen, such as 20-50%, 20-40%,20-35%, 25-35%, such as 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%,34%, and 35% w/w.

The process typically involves the containment unit being rigid, andcomprising at least one opening and one closure-unit and such that themixing proceeds without loss of liquid.

The second volume is typically less than 85% of the first volume,preferably less than 80%, even more preferably less than 75% of thefirst volume, such as 70%, 65%, 60%, 55%, or 50% of the first volume.

The process for preparing a haemostatic product may comprise the stepsof:

i) providing a containment unit having a first internal volume and atleast one aperture for opening said aperture closed by a closure-unitand comprising a second volume of 15 haemostatic agent, said secondvolume being no more than 90% of the first volume;

ii) adding a third volume of liquid to said containment unit; and

iii) mixing the haemostatic agent and the liquid by shaking thecontainment unit.

The sterile containment unit may further comprise an outer packagingdefining a sterile barrier seal for enclosing said containment unit, asdescribed supra.

A further aspect of the invention relates to a method of promotinghaemostatis comprising administering an effective amount of a putty-likepaste comprising 20-35% wt/wt collagen powder, such as 25-33%, such as25%, 26%, 27%, 28%, 29%, 30%, 31%, 32% and 33% of collagen to a patientin need of haemostatis, wherein the putty-like paste is preparedaccording process as defined supra.

The invention may be for use in any array of surgical procedures whereinbleeding or fluid control is preferred, such as in orthopedicprocedures, such as laminectomy, total hip replacement and hiprevisions, knee surgery, spinal fusion; in cardiothoracic/cardiovascularprocedures such as CABGs, valve replacements, aotic surgery, abdominalaortic aneurisms, carotid endarterectomy, and femoral-popliteal bypass,amongst others.

A still further object of the invention is directed to the use of acontainment unit defining a first internal volume and a second volume ofcollagen or collagen-derived powder for the preparation of a haemostatickit; wherein the second volume is less than 90% of the first volume suchas 85% of the first internal volume, such as less than 80% of the firstvolume, preferably less than 75%, even more preferably less than 70% ofthe first volume 65%, 60%, 55%, or 50% of the first volume.

The invention is further defined by the Examples.

EXAMPLES Example 1

Product and Preparation

Clinical data (Example 2) was obtained on powder prepared from millingsheets of Surgifoam® sponge under a controlled process to produce aproduct meeting the following specification:

The powder is a porcine gelatin based powder, off white in colour.

10% volume is less than approximately 90 μm;

50% volume is less than approximately 350 μm;

90% volume is less than approximately 700 μm;

as determined by laser diffraction.

The milled product is collected under slight negative pressure to avoidparticulate emission in the area and filled into a primary container,such as by using a hopper and scoop filling operation or by usingpharmaceutical cGMP standard auger filling equipment.

The fill will be such that to be less than 75% of the volume of theprimary container and checked by electronic scales so as to meet todesired pre-determined weight. A closure will be applied.

The container will then be placed in a foil/film pouch which is sealedwith a rotary heat sealer to form a moisture protection poach.

Alternatively, the batched containers will then be transferred to ablister packing room, such as a Multivac blister packing, where eachcontainer is packaged into a PETG/PE blister package. The blister packedproduct is loaded into irradiation boxes and subjected to pre-determinedlevels of e-beam irradiation.

Example 2

Clinical Data

Clinical tests for effectiveness on general surgical procedures as wellas cardiovascular and orthopaedic surgical procedures were performed.

Study Design

An open label, randomised, controlled, multi-centre, unmasked study wasconducted to evaluate safety and effectiveness of two haemostaticagents. The study compared the SURGIFOAM sponge from which thehaemostatic powder is prepared to an absorbable gelatin sponge currentlylegally marketed in the USA. The primary objective was to examine theeffectiveness as measured by haemostatis within 10 minutes ofapplication.

Study Results

Two hundred and eighty one patients were enrolled in to the study andreceived study treatment. The haemostatis data was collected immediatelyduring the surgery and the patients examined at 2 to 4 weeks and againat 6 to 8 weeks in order to obtain safety data. The effectiveness datais summarised in Table 1.

TABLE 1 General Cadiovascular Orthopaedic Total Minutes Device % % % % 3Surgifoam 65.6 57.4 91.7 64.0 Control 66.2 62.9 100 66.9 6 Surgifoam98.4 80.9 100 90.1 Control 95.4 91.9 100 94.2 10 Surgifoam 100 89.7 10095.1 Control 95.4 96.8 100 96.4

Statistical analysis showed that SURGIFOAM and the control sponge wereequivalent in the ability to achieve haemostatis within 10 minutes.

Example 3

Evaluation of the Medical Device

Goal

The purpose of this study was to measure both surgeons and operatingroom nurses' perception of the device in terms of control of sterilityand ease of preparation.

Method/Sample

12 interviews were conducted with operating room nurses who usehaemostatic agents regularly.

Summary of Results

The surgeons and the nurses had complete acceptance and preference for akit as defined by the present invention over conventional products.

Conventional Practice

Mixing of Conventional Products:

-   -   use of finger in a container separate than the agents container    -   use of forceps or pickups or other surgical instruments in a        container separate than the agents container

Disadvantages of Conventional Products:

-   -   possible contamination in transferring product to separate        mixing container    -   bad smell    -   non-sterile packaging    -   powder is readily air-borne during opening and transfer process    -   non-sterile container risks contamination of sterile field    -   lengthy preparation due to requirement of additional bowl    -   breathing in of air-borne powder    -   wasted product in dispensing to mixing container

A medical device of the present invention was presented to the surgeonsand the nurses of the test study. The response was such that theinvention favourably addressed most or all of the disadvantaged ofconventional products.

Example 4

Sealed Pouches of Laminated Foil for Containment Unit

The pouch must be able to endure radiation sterilisation at 3.5 Mrad(Beta) Bioburden less than 100 CFU/unit. With the Pouch A, suitablecontainment comprising 1 gram of powder allowed for the storage of thepowder and the containment unit as sterile for extended periods of time(typically at least 4 years) without loss in the quality of thematerials.

Material: PET   12 microns Foil 8.75 microns Clear EZ Peel   50 micronsSize: Width  6.5 inches Length   10 inches,

with a thumbnotch at the chevron end to allow for easy opening.

Provider Perfecseal

Items

1. A medical device comprising:

i) a containment unit defining a first internal volume; said containmentunit being comprised of a material substantially impermeable to fluid;

ii) a haemostatic agent of a second volume contained in said containmentunit, said second volume being less than 90% of the first volume.

2. The medical device according to item 1, wherein said second volume isless than 85%, of the first volume, preferably less than 80%, even morepreferably less than 75% of the first volume, such as 70%, 65%, 60%, 55%or 50% of the first volume.

3. The medical device according to any one of items 1 to 2, wherein thehaemostatic agent is collagen or collagen-derived powder.

4. The medical device according to item 3, wherein said collagen orcollagen-derived powder is gelatin.

5. The medical device according to any one of the preceding itemsfurther comprising iii) a third volume of a liquid

6. The medical device according to item 5, wherein the liquid is blendedwith the haemostatic agent

7. The medical device according to item 5, wherein the liquid is in aunit physically separated from the haemostatic agent

8. The medical device according to item 5, wherein the liquid is in asecond containment unit whose internal volume is physically separatedfrom the first containment unit.

9. The medical device according to any one of preceding items furthercomprising thrombin or a containment unit containing thrombin.

10. The medical device according to item 5, wherein the liquid isselected from the group consisting of water and an aqueous solution.

11. The medical device according to item 10, wherein the aqueoussolution comprises an isotonicity-adjusting agent.

12. The medical device according to item 11, wherein the isotonicityadjusting agent is sodium chloride.

13. The medical device according to any one of items 5 to 12, whereinthe liquid comprises thrombin and/or a bacteriostatic agent.

14. The medical device according to items 4 to 13, wherein the liquid issterile.

15. The medical device according to any one of preceding items, whereinsaid containment unit comprises at least one opening and at least oneclosure-unit for closing the at least one opening.

16. The medical device according to item 15, wherein the closure-unitcomprises a rupturable membrane.

17. The medical device according to any one of items 15 to 16, whereinthe closure-unit defines an internal volume suitable for containing aliquid.

18. The medical device according to items 4 to 12, wherein the thirdvolume of liquid is less than 20% of the second volume.

19. The medical device according to any one of preceding items, whereinsaid collagen or collagen-derived powder is in an amount from about 0.1to 50 g, preferably from about 0.2 to 20 g, even more preferably fromabout 0.4 to 10 g, most preferably from about 0.5 to 5 g, such as 0.75,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 g.

20. The medical device according to any one of preceding items furthercomprising an outer packaging defining a sterile barrier seal forenclosing said containment unit.

21. The medical device according to any one of preceding items, whereinthe containment unit is sterile.

22. The medical device according to any one of items 20 to 21 whereinthe containment unit-facing side of the outer packaging and thecontainment unit are sterile.

23. A haemostatic kit comprising

-   -   i) a containment unit said containment unit defining a first        internal volume and    -   ii) a second volume of haemostatic agent    -   wherein the second volume relative to the first internal volume        is such that the kit is suitable adding a third volume of liquid        to said second volume and suitable for mixing said haemostatic        agent within said containment unit.

24. The haemostatic kit according to item 23, wherein the third volumeis an amount so as to obtain a putty-like paste from the haemostaticagent, wherein a putty-like paste of the haemostatic agent comprises20-33% w/w of collagen powder.

25. A method according to item 23, wherein said mixing proceeds withoutpresent exposure to an environment external to that of the containmentunit.

26. The haemostatic kit according to any one of items 23 to 24, whereinthe containment unit is rigid, comprises at least one opening and oneclosure-unit and such that the mixing proceeds without loss of liquid.

27. The haemostatic kit according to any one of items 23 to 26, whereinthe second volume of haemostatic agent is less than 90% of the firstinternal volume.

28. The haemostatic kit according to item 27, wherein said second volumeis less than 90% of the first volume, preferably less than 85%, evenmore preferably less than 80% of the first volume, such as 75%, 70%,65%, 60%, 55% or 50% of the first volume.

29. The haemostatic kit according to any one of items 23 to 27, whereinthe haemostatic agent is collagen or collagen-derived powder.

30. The haemostatic kit according to item 29, wherein said collagen orcollagen-derived powder comprises essentially of gelatin.

31. The haemostatic kit according to item 26, wherein the closure-unitcomprises a rupturable membrane.

32. The haemostatic kit according to any one of items 23 to 31 furthercomprising iii) said third volume of a liquid

33. The haemostatic kit according to item 32, wherein the liquid isblended with the haemostatic agent.

34. The haemostatic kit according to item 32, wherein the liquid is in aunit physically separated from the haemostatic agent.

35. The haemostatic kit according to item 32, wherein the liquid is in asecond containment unit whose internal volume is physically separatedfrom the first containment unit.

36. The haemostatic kit according to any one of items 23 to 35 furthercomprising thrombin or a containment unit containing thrombin.

37. The haemostatic kit according to item 32, wherein the liquid isselected from the group consisting of water and an aqueous solution.

38. The haemostatic kit according to item 37, wherein the aqueoussolution comprises an isotonicity-adjusting agent.

39. The haemostatic kit according to item 38, wherein the isotonicityadjusting agent is sodium chloride.

40. The haemostatic kit according to any one of items 23 to 39, whereinthe liquid comprises thrombin and/or a bacteriostatic agent.

41. The haemostatic kit according to items 23 to 40, wherein the liquidis sterile.

42. The haemostatic kit according to any one of preceding items, whereinsaid containment unit comprises at least one opening and at least oneclosure-unit for closing the at least one opening.

43. The haemostatic kit according to item 26, wherein the closure-unitdefines an internal volume suitable for containing a liquid.

44. The haemostatic kit according to items any one of items 23 to 43,wherein liquid is an amount less than 20% of the second volume.

45. The haemostatic kit according to any one of items 23 to 44, whereinsaid haemostatic agent is in an amount from about 0.1 to 50 g,preferably from about 0.2 to 20 g, even more preferably from about 0.4to 10 g, most preferably from about 0.5 to 5 g, such as 0.75, 1, 1.5, 2,2.5, 3, 3.5, 4, 4.5, and 5 g.

46. The haemostatic kit according to any one of items 23 to 45 furthercomprising an outer packaging defining a sterile barrier seal forenclosing said containment unit.

47. The haemostatic kit according to any one of items 23 to 45, whereinthe containment unit is sterile.

48. The haemostatic kit according to any one of items 23 to 47, whereinthe containment unit-facing side of the outer packaging and thecontainment unit are sterile.

49. A process for preparing a haemostatic product comprising the stepsof:

-   -   i) providing a sterile containment unit having a first internal        volume and at least one aperture for opening and comprising a        second volume of haemostatic agent, said second volume being no        more than 90% of the first volume;    -   ii) adding a third volume of liquid to said containment unit;        and    -   iii) mixing the haemostatic agent and the liquid by shaking the        containment unit.

50. The process for preparing a haemostatic product according to item49, wherein the mixing proceeds without substantial exposure of saidhaemostatic agent and said liquid to an environment external to that thecontainment unit.

51. The process for preparing a haemostatic product according to any oneof items 49 to 50, wherein the haemostatic agent is collagen orcollagen-derived powder.

52. The process for preparing a haemostatic product according to item51, wherein said collagen or collagen-derived powder comprisesessentially of gelatin.

53. The process for preparing a haemostatic product according to any oneof items 49 to 52, wherein said haemostatic product is in the form of aputty-like paste comprising 20 to 99% w/w of collagen.

54. The process for preparing a haemostatic product according to any oneof items 49 to 53, wherein the containment unit is rigid, comprises atleast one opening and one closure-unit and such that the mixing proceedswithout loss of liquid.

55. The process for preparing a haemostatic product according to any oneof items 49 to 54, wherein said second volume is less than 85% of thefirst volume, preferably less than 80%, even more preferably less than75% of the first volume, such as 70%, 65% or 60% of the first volume.

56. The process for preparing a haemostatic product according to item 49comprising the steps of:

-   -   i) providing a containment unit having a first internal volume        and at least one aperture for opening said aperture closed by a        closure-unit and comprising a second volume of haemostatic        agent, said second volume being no more than 90% of the first        volume;    -   ii) adding a third volume of liquid to said containment unit;        and    -   iii) mixing the haemostatic agent and the liquid by shaking the        containment unit.

57. The process for preparing a haemostatic product according to item 49wherein the sterile containment unit is further comprises an outerpackaging defining a sterile barrier seal for enclosing said containmentunit.

58. The process according to item 57, wherein the containment unitcomprises a surface which makes at least partial contact with the outerpackaging the containment-unit contacting side is sterile.

59. A method of promoting haemostatis comprising administering aneffective amount of a putty-like paste comprising 20 to 33% w/w ofcollagen to a patient in need of haemostatis, wherein the putty-likepaste is prepared according process defined in to any one items 49 to58.

60. Use of a containment unit defining a first internal volume andsecond volume of collagen or collagen-derived powder for the preparationof a haemostatic kit wherein the second volume is less than 90% of thefirst volume.

1. A medical device for preparing a haemostatic paste, consisting of: i)a containment unit defining a first internal volume and being comprisedof a material impermeable to a fluid, wherein the containment unitfurther comprises an opening to an external environment and aclosure-unit for closing the opening, wherein the opening is re-closablewith the at least one closure-unit, and ii) a sterile haemostatic agentin powder form contained in said containment unit and having a secondvolume of less than 90% of the first internal volume of the containmentunit; wherein said sterile haemostatic agent is capable of forming aputty-like paste in the presence of a third volume of liquid; and iii)an outer packaging defining a sterile barrier seal enclosing saidcontainment unit; wherein the remaining volume of at least 10% of theinternal volume is a void volume allowing for the addition of a thirdvolume of liquid from an external environment to the sterile haemostaticagent in powder form through the opening and mixing of the sterilehaemostatic agent in powder form and the added liquid within thecontainment unit without present exposure to an environment external tothat of the containment unit.
 2. The medical device according to claim1, wherein the at least one opening is separated from said externalenvironment by the closure-unit during the mixing.
 3. The medical deviceaccording to claim 1, wherein said haemostatic agent in powder form isgelatine.
 4. The medical device according claim 1, wherein saidhaemostatic agent in powder form is collagen. 5-6. (canceled)
 7. Themedical device according to claim 1, wherein the volume of saidhaemostatic agent is less than 80% of the internal volume of thecontainment unit.
 8. The medical device according to claim 1, whereinsaid haemostatic agent is provided in an amount from about 0.5 to 5 g.9. (canceled)
 10. The medical device according to claim 1, wherein thehaemostatic agent is provided in an amount of about 1 g, and the volumeof the containment unit is 50 to 100 cubic centimetres.
 11. The medicaldevice according to claim 1, wherein said containment unit is rigid orsemi-rigid and comprises a wide-mouth opening.
 12. The medical deviceaccording to claim 11, wherein said containment unit and closure unit ismade of a material selected from the group of polypropylene,polyethylene, PVC and PET.
 13. The medical device according to claim 12,wherein the containment unit is made from substantially rigidpolyethylene or polypropylene, and has a single opening which may besealed with a threaded, polyethylene or polypropylene closure.
 14. Themedical device according to claim 1, wherein said outer packagingcomprises a laminated foil pouch.
 15. A haemostatic kit comprising i)the medical device according to claim 1, and ii) a third volume of asterile liquid in a second containment unit whose internal volume isphysically separated from the containment unit of the medical device,wherein the kit is suitable for adding said liquid to said containmentunit of the medical device.
 16. The haemostatic kit according to claim15, wherein said third volume of liquid is selected from the group ofwater, an aqueous solution, saline, an aqueous solution comprising anisotonicity-adjusting agent, an aqueous solution comprising thrombinand/or an aqueous solution comprising a bacteriostatic agent.
 17. Aprocess for preparing a haemostatic paste comprising the steps of: A)removing the outer packaging of the medical device according to claim 1,B) opening the containment unit to the external environment, C) adding asterile liquid to said containment unit, D) re-closing the at least oneopening of the containment unit by the closure-unit, and E) mixing theliquid and the sterile haemostatic agent contained in the containmentunit without substantial exposure of said haemostatic agent and saidliquid to an environment external to the containment unit, therebypreparing the haemostatic paste.
 18. The process according to claim 17,wherein said sterile liquid of step C) is added by pouring the liquidthrough the at least one opening of the containment unit.
 19. Theprocess according to claim 17, wherein said mixing of step E) isperformed by shaking the containment unit.
 20. The process according toclaim 17, wherein the containment unit is transferred into a sterilefield before opening said containment unit in step B).
 21. The processaccording to claim 17, wherein the sterile liquid of step C) is added ina volume less than 35% of the second volume of haemostatic agent. 22.The process according to claim 17, wherein the haemostatic paste of stepE) is a putty-like paste.